Project Summary Type 1 diabetes (T1DM) is becoming an increasing problem for the VA as a result of the influx of younger veterans into the system. Insulin monotherapy has been the only treatment for T1DM since the discovery of insulin in 1922. We have reported that induction of hyperleptinemia in totally insulin deficient rodents completely reverses the clinical and laboratory manifestations of uncontrolled diabetes and restores otherwise moribund rodents to full health. We find that leptin recapitulates every desirable action of insulin and opposes its undesirable lipogenic and cholesterogenic actions. The glycemic variability with insulin treatment of T1DM results from the disparate insulin requirements of the various target tissues of the hormone, which cannot be met by a single concentration of peripherally injected insulin, together with the wide fluxes in fatty acids. Leptin, by suppressing both glucagon and fatty acids, can overcome both of these insulin defects. Now we wish to determine the mechanisms of these remarkable effects and begin translation of our findings to humans. It if works as effectively as in rodents, it should improve the quality of diabetic life through increased glycemic stability, fewer insulin injections, blood glucose sampling, and a reduction in lipogenesis and cholesterogenesis and their macrovascular diseases. PUBLIC HEALTH RELEVANCE: Project Narrative Relevance of the proposed research to veterans health and/or healthcare issues: The ability to treat and restore to full health the new generation of type 1 diabetic veterans and spare them the hardships of multiple insulin injections and constant risk of hypoglycemia, would be a major step forward in enhancing the quality of their lives. Furthermore, the antilipogenic and anticholesterogenic activities of leptin treatment should reduce the high incidence of atheromatous disease in type 1 patients. If it works in humans, as it has in rodents, the treatment of diabetes will have been revolutionized for the first time in eighty-seven years.